Clotting Factor Drug Doesn't Block ICH Expansion

HOUSTON -- Giving a hemostatic agent to patients with imaging signs of ongoing intracerebral hemorrhage (ICH) did not stem its expansion or improve outcomes, pooled results from two trials showed.

Median intracerebral hematoma volume was 22 mL at 24 hours in patients given recombinant factor VIIa (rFVIIa, NovoSeven) compared with 29 mL in those given placebo (P=0.9), David Gladstone, MD, PhD, of the University of Toronto, and colleagues reported here at the International Stroke Conference.

Nor was there a significant treatment effect of systemic administration of the clotting factor on:

• Total 24-hour intracerebral and intraventricular volume, even after adjustment for factors including baseline size and onset to needle time
• Proportion of patients with more than 6 mL or 33% growth in the hemorrhage at 24 hours, with or with out adjustment
• 90-day mortality
• Proportion of patients with a modified Rankin score of 5 to 6 at 90 days

The researchers chalked up the findings to a smaller than expected ICH expansion and underpowered sample size and, more importantly, that the treatment was likely administered too late after the majority of expansion had already occurred.

Among those treated within 3 hours of stroke onset, absolute volume increase was a median 0.9 mL with rFVIIa versus 4.4 mL with placebo, although not a significant difference (P=0.8).

Gladstone noted that while only hypothesis-generating at this point, it was an encouraging hint. "But it does support our hypothesis that if there is to be a benefit, it will be in patients treated very early," he stated.

If a 90-minute treatment target could be hit in the original thrombolytic trial for acute ischemic stroke, surely it could be done for ICH as well, Gladstone told reporters at a press briefing. Diagnosis and administration in the ambulance might be the next step, he suggested.

However, the logistics would be a challenge, said co-author Matthew Flaherty, MD, of the University of Cincinnati.

That speed is an issue is not surprising, commented conference chair and press briefing moderator Bruce Ovbiagele, MD, of the Medical University of South Carolina in Charleston.

But the trials did validate the spot sign used to select patients, as this predicted larger hematoma volumes and greater expansion by 24 hours, after adjustment for baseline and onset to CT time.

"The attraction of the SPOTLIGHT/STOP-IT trials is here you have a devastating condition with no treatment whatsoever, and you potentially have an imaging marker that is widely available," Ovbiagele said.

"There's promise here, it's just a question of honing down on the right eligibility criteria," agreed Philip Gorelick, MD, MPH, of the Michigan State University in Grand Rapids and an American Stroke Association spokesperson.

The parallel, similarly designed SPOTLIGHT and STOP-IT trials included a total of 69 non-anticoagulated patients in the U.S. and Canada with a positive "spot sign" on CT angiography randomly assigned to intravenous rFVIIa (a single bolus of 80 µg/kg) or placebo within 6 hours of onset. Another 73 spot-negative patients were prospectively observed for comparison.

The treatment showed no significant safety concerns, according to the researchers, with no myocardial infarction or pulmonary embolism within 4 days and the only ischemic stroke occurring in the placebo group. There was a possible middle cerebral artery thrombosis seen on imaging in the treatment group, but it was asymptomatic and diffusion-weighted imaging negative.

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